This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project is aimed at determining the molecular mechanisms that mediate acute and long term actions of alcohol on the brain. Identifying the molecular targets of alcohol is fundamental to developing strategies for preventing the development of abusive use of alcohol, and for designing therapies for alcohol addiction. We will use patch-clamp recording from granule cells in acutely prepared slices of cerebellum to identify molecular and cellular responses to acute alcohol exposure. Specifically, we are testing the role of four molecular mechanisms, which are known to interact with the GABAergic system in the cerebellum, in mediating the alcohol-induced increase in cerebellar granule cell GABAergic transmission. We will also determine if chronic, voluntary alcohol consumption leads to long-term molecular adaptations in cerebellar GABAergic transmission. Molecular adaptation to chronic alcohol consumption may contribute to withdrawal symptoms, and hence contribute to addiction. Finally, we will determine if individual variability in cerebellar granule cell sensitivity to alcohol underlies individual variability in sensitivity to alcohol-induced motor impairment. Sensitivity to alcohol-induced motor impairment is known to be a heritable predictor of alcohol abuse in humans, and thus determining its molecular underpinnings should help screen humans for predilection for alcohol abuse. The successful completion of the proposed experiments will improve our understanding of the molecular targets of alcohol, and will identify molecular aspects of cerebellar contribution to alcohol abuse and addiction.